Hashimoto et al. in U.S. Pat. No. 4,335,211, incorporated herein by reference, disclose a class of 1-carbacephalosporins having desirable antibiotic and oral activity characteristics. These compounds are currently being evaluated for the treatment of various conditions such as the common upper- and lower-respiratory tract infections caused by the pathogen H. influenza. One such compound, 7-(R)-phenylglycinamido-3-chloro-1-azabicyclo[4,2,0]-oct-2-en-8-on-2-carbo xylic acid, known as loracarbef or LY163892, has shown activity against a broad spectrum of bacteria in laboratory tests. Loracarbef has proven to be relatively stable compound which exhibits high blood levels and a relatively long half life.
The 1-carbacephalosporins thus far have not been obtained from natural sources, for example, as microbial metabolites. Accordingly, methods for the total synthesis of these promising compounds and for intermediates to these compounds are highly desirable, particularly methods which are adaptable to large scale manufacture, provide good yields, and reduce the cost of manufacture.
More particularly desired key intermediates to such compounds have the formula ##STR1## wherein R.sup.1 is 2-furyl, phenyl, substituted phenyl, carboxy or protected carboxy, R.sup.2 is C.sub.1 -C.sub.6 alkyls, hydrogen, or a carboxy protecting group and X is an acid capable of forming acid additions salts. These intermediates represented by formula (IA) can then be further synthesized to form 1-carbacephalosporins, as disclosed generally in Evans et al., U.S. Pat. No. 4,665,171, incorporated herein by reference.
A particular compound represented by formula (IA), a saturated methyl ester oxalate (IB), may be formed by a process as follows in Scheme 1. ##STR2##
The process in Scheme 1 has approximately a 24 hour cycle time due, at least in part, to a relatively slow filtration of the compound as represented by formula (IB). Also, the intermediate represented by formula (III) is isolated before the ensuing hydrogenation step, and this also adds to the cycle time. Further, the process in Scheme 1 provides yield of the compound as represented by formula (IB) of approximately 20%. This relatively low yield may be due to ring cleavage and more particularly cleavage of the azetidinone ring resulting in an undesired compound having the formula ##STR3##